News Physiol Sci 13: 123-131, 1998;
1548-9213/98 $5.00
News in Physiological Sciences, Vol. 13, No. 3, 123-131,
June 1998
© 1998 Int. Union Physiol. Sci./Am. Physiol. Soc.
The Molecular Physiology of Sodium- and Proton-Coupled Solute Transporters
Angela Steel and
Matthias A. Hediger
M. A. Hediger is in the Harvard Institutes of Medicine, 77 Ave. Louis Pasteur, Rm. 570, Boston, MA 02115, USA (E-mail: mhediger{at}rics.bwh.harvard.edu). A. Steel is at SmithKline Beecham Pharmaceuticals, 1250 S. Collegeville Rd., Collegeville, PA 19426-0989, USA.
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Abstract
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The expression of cloned Na+- and H+-coupled solute transporters in Xenopus laevis oocytes has permitted detailed molecular and biophysical analysis and illuminated unique mechanistic features. The identification of missense mutations in inherited diseases and site-directed mutagenesis studies have enhanced our understanding of their roles in physiological and pathological processes.
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Introduction
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The recent progress in molecular biology of membrane transport proteins has yielded a wealth of new information on transport mechanisms, biological functions, and therapeutic implications. In this review, we will focus on two transporter families, the Na+-glucose and the H+-oligopeptide cotransporters, which have undergone extensive molecular and biophysical characterization, most notably with respect to their stoichiometry and transport mechanisms. Examination of these archetypal transporters has revealed unifying properties, common to both Na+- and H+-coupled transporters, as well as significant mechanistic differences. This information is discussed in relation to the physiology and pathophysiology of epithelial membrane transport.
In both prokaryotes and eukaryotes, the electrochemical gradients of Na+ and H+ play major roles in energizing uphill cellular solute uptake. In mammals, the inwardly directed Na+ electrochemical gradient is maintained by the Na+-K+-ATPase present in the basolateral membrane of epithelial cells (Fig. 1
). There is also an H+ electrochemical gradient across the intestinal brush-border membrane in the lumen-to-cytoplasm direction. The intracellular pH of the enterocyte is ~7.0–7.2, whereas the pH of the unstirred layer in close proximity to the external surface of the brush-border membrane is ~6.0, resulting in a ~10-fold difference in H+ concentration between the intestinal lumen and the cytoplasm. The electrochemical H+ gradient is generated and maintained by the combined action of the Na+/H+ exchanger in the brush-border membrane and the Na+-K+-ATPase in the basolateral membrane (Fig. 1).
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FIGURE 1. Active transport of sugars and oligopeptides into intestinal epithelial cells. Schematic diagrams illustrate proposed mechanisms of transepithelial transport. A: Na+-coupled glucose transport. Brush-border Na+-glucose cotransporter (SGLT) transports D-glucose and D-galactose from the lumen (left) into the cell utilizing Na+ gradient generated by Na+-K+ ATPase. Sugars then exit at the basolateral side (right) via the passive glucose transporter (GLUT). B: H+-coupled oligopeptide transport. Dietary protein is hydrolyzed by membrane-bound peptidases to form oligopeptides that are transported into enterocytes by H+-oligopeptide cotransporter (PepT). This process is driven by the proton-motive force, which is generated by apical membrane Na+/H+ exchanger and basolateral Na+-K+ ATPase. Partial degradation of the peptides to amino acids within the cell leads to their facilitated exit by specific amino acid transporters on the basolateral membrane. Exit of peptides across basolateral membrane may also occur by a hypothetical basolateral transporter.
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The known members of the Na+-glucose and H+-oligopeptide transporter families are summarized in Table 1. The Na+-coupled SGLT family includes the high-affinity Na+-glucose transporters SGLT1 (5, 6), the two low-affinity isoforms SGLT2 and SGLT3 (formerly known as porcine SGLT2) (6), the inositol transporter SMIT (7), the iodide transporter NIS (1), and the multivitamin transporter (SMVT) (15). The oligopeptide transporter family includes the oligopeptide transporters PepT1 (3) and PepT2 (8).
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Na+-glucose transporters
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In mammals, the capture of glucose from the diet and the glomerular filtrate is a fundamentally important step that requires specific membrane transporters. The primary structure of the intestinal Na+-coupled glucose transporter SGLT1 was obtained by expression cloning using Xenopus laevis oocytes (5, 6). The SGLT1 protein has 662 amino acid residues with a molecular mass of 74 kDa and at least 12 transmembrane domains (Fig. 2A). Functional characterization identified this clone as the high-affinity glucose transporter [Michaelis-Menten constant (Km) for D-glucose was 0.3 mM in rabbits and 0.8 mM in humans] responsible for the absorption of dietary glucose and galactose across the brush-border membranes of intestinal enterocytes (Fig. 1
). On the basis of studies of rat intestine, in situ hybridization with SGLT1 mRNA shows expression predominantly in the crypts and lower part of each villus. As enterocytes migrate from the crypts, they differentiate and synthesize SGLT1 protein, which is primarily expressed at the villus tips (for review, see Ref. 6).
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FIGURE 2. Structural models of SGLT1 and PepT1 with mutations indicated. A: in patients with glucose-galactose malabsorption, a series of missense mutations were found that showed reduced sugar uptake when expressed in Xenopus oocytes yet retained protein levels similar to wild type. These are indicated on the structural model of SGLT1. Additional site-directed mutants shown in boxes (D176A, R427A, and Q457R) displayed altered kinetic and biophysical properties (see text for details). B: PepT1 model, showing the histidine residues that have recently been subjected to mutagenesis. H57 residue was found to be obligatory for transport in all 3 PepT1 species tested (human, rabbit, and rat species), whereas H121 displayed no transport activity in rat PepT1. H260 mutants did not alter the transport characteristics and are unlikely to play any significant role in substrate binding or translocation. In both models, amino acid residues are defined using the single-letter code and residue number, and branched tree represents N-glycosylation sites.
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In kidney, D-glucose is freely filtered at the glomerulus and then almost completely extracted from the urine in the proximal tubule and returned to the blood. Approximately 90% of the filtered glucose is reabsorbed in the early S1 segment of the proximal tubule by a low-affinity Na+-glucose transporter termed SGLT2 (Km for D-glucose was ~2 mM for human SGLT2). The high-affinity SGLT1 transporter located in the proximal tubule S3 segments absorbs any glucose that escapes the S1 segment. The Na+-to-glucose coupling ratio of 2:1 for SGLT1 is consistent with its role in the absorption of sugar against a large concentration gradient. By contrast, the low-affinity transporters SGLT2 and SGLT3 have Na+-to-glucose coupling ratios of 1:1 and thereby have a much lower concentrating capacity than SGLT1.
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Physiological and pathophysiological implications of Na+-glucose transporters
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Evidence for the significance of Na+-glucose cotransport as the sole glucose absorptive pathway in the intestinal brush-border membrane is provided by transport defects in SGLT1, which lead to familial glucose-galactose malabsorption (GGM). The accumulation of intestinal sugars in patients with GGM results in a reversal of osmotic flow, which causes severe diarrhea unless glucose and galactose are removed from the diet. A spectrum of mutations responsible for malabsorption has been identified in SGLT1 (Fig. 2A). Most are in the coding region and produce mutant or truncated proteins (10). Mutations or alterations in the expression of the renal low-affinity isoform SGLT2 may account for familial renal glycosuria, a relatively benign syndrome restricted to the kidneys, although further verification of this hypothesis is still required.
Increased Na+ and glucose reabsorption by the renal Na+-glucose cotransporters SGLT1 and SGLT2 may contribute significantly to the pathogenesis of the kidney disease in diabetes mellitus (for review, see references in Ref. 6).
In the intestinal brush-border membrane, Na+-coupled solute transport via SGLT1 facilitates fluid absorption. Na+ that enters epithelial cells through Na+-coupled transport is pumped into the blood by the Na+-K+-ATPase, resulting in a transepithelial Na+ flux that generates an osmotic gradient and drives fluid absorption. The presence of luminal glucose and galactose stimulates transepithelial salt and water absorption. Recent studies furthermore showed that SGLT1 itself is capable of transporting water, indicating that Na+-coupled sugar transport directly contributes to water absorption (11).
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Functional characteristics of SGLT1 and SGLT2
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Our knowledge of the structure-function relationship of SGLT1 has been advanced with the identification of missense mutations of SGLT1 in GGM patients. These mutations concern predominantly charged or polar residues which display nonrandom distribution in the sequence, with eight of the mutations lying in two conserved hot spots (Fig. 2A, residues 289–304 and 369–405) (10). When the mutant proteins were expressed in Xenopus oocytes, 15 of them showed defective sugar transport, yet were present in the membrane at levels comparable to the wild type (Fig. 2A). Two additional mutations, A304V and R499H, were studied in detail and showed impaired trafficking of the cotransporters to the plasma membrane, suggesting a role for these polar and charged residues in the retention of protein conformation due to electrostatic interactions (10). Another residue implicated in membrane targeting is residue R427, since the R427A mutant SGLT1 protein accumulates beneath the membrane surface.
Mutagenesis has also led to the identification of residues that participate in substrate and inhibitor binding. Sugar transport displayed by Q457A was reduced, and R499H showed a dramatic increase in Km, suggesting that these residues lie close to the sugar binding site. The affinity of D176A for the specific competitive inhibitor phlorizin was increased four- to sixfold, making it a candidate residue in inhibitor interaction. Interestingly, results also link D176 with the conformational changes responsible for the reorientation of the unloaded carrier in the membrane because the rate constants for this step were altered profoundly, whereas other kinetic parameters for sugar transport were only modestly affected (Fig. 3A).
Additional information on the structure-function relationship of Na+-glucose transporters was obtained from a study of a chimera containing the amino terminus of SGLT3 (amino acids 1–380) and the carboxy terminus of SGLT1 (amino acids 381–662). This chimera displayed substrate specificity characteristics similar to the high-affinity transporter SGLT1, suggesting that the carboxy terminus of the protein is responsible for sugar binding. Further support for this hypothesis came from studies with a construct containing putative helices 9–12 of SGLT1 (14). This truncated protein was capable of Na+-independent sugar influx, characteristic of a specific, low-affinity glucose uniporter, suggesting that the carboxy-terminal helices form the sugar permeation pathway.
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H+-oligopeptide transporters
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The breakdown of dietary proteins in the gastrointestinal tract by brush-border membrane-bound peptidases (Fig. 1) produces a rich source of mixed oligopeptides. In addition to those transporters for free amino acids, initial studies with intestinal and renal brush-border membrane vesicles identified electrogenic, H+-oligopeptide transporter activity. This led to the expression cloning of a transporter, designated PepT1, from rabbit intestine. The coupling of PepT1 to H+ rather than to Na+ was demonstrated in Xenopus oocytes expressing PepT1 when peptide-evoked inward currents were associated with intracellular acidification (3). PepT1 is a 707-amino acid residue protein with 12 putative transmembrane domains (Fig. 2B), and hybrid depletion studies suggested that PepT1 is the predominant intestinal transporter, although there is some evidence for additional transporters, including a basolateral exit mechanism for peptides (Fig. 1) (for review, see Ref. 12). Studies to examine the expression of the peptide transporters have revealed that PepT1 is expressed predominantly in intestine and to a lesser degree in kidney and liver. The PepT1 transcript was most abundant in enterocytes of duodenum and jejunum, consistent with its role as the principal route of absorption for dietary digestion products. With the use of an antibody against the rat H+-oligopeptide transporter, PepT1 was localized to the brush-border membrane of enterocytes with particular enrichment in the tips of villus cells.
A second peptide transporter, PepT2, which displays 50% sequence identity to PepT1, was cloned from human kidney by homology screening using PepT1 cDNA as a probe (8). PepT2 is expressed in kidney, brain, liver, and testes but not in the intestine. Both transporter isoforms are proton coupled, exhibit electrogenic transport, and share similar substrate profiles transporting diverse di- and tripeptides and peptidomimetic drugs. However, PepT2 displays greater affinity for many substrates and appears to differentially recognize certain antibiotics compared with PepT1.
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Substrates for the H+-oligopeptide transporters and their therapeutic implications
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The capacity of PepT1 and PepT2 to transport almost any di- and tripeptide, regardless of charge, size, and composition, is a unique property of these transporters (3, 12). Single amino acids and larger oligopeptides (>4-mer) are excluded. Bulky hydrophobic side chains and free amino and carboxy termini are preferred, since modification of these groups greatly reduced the affinity. A terminal carboxy group seems to be a basic structural requirement, possibly permitting binding to a positively charged residue within the transport protein. The transporters are partially stereoselective, since peptides containing L-amino acids show greater affinity than D-amino acids. The broad substrate range has been exploited in terms of formulating enteral and parenteral solutions, since short-chain peptides are often considered as viable substitutes for free amino acids. The low osmolality of peptide-based parenteral solutions provides an added advantage, especially in patients with severe fluid restriction.
In addition to oligopeptides, the proton-coupled peptide transporters also catalyze the transport of many biologically active and therapeutically important peptidomimetics. Many orally active antibiotics (e.g., the amino penicillin, cyclacillin, and the amino cephalosporins, cephradine and cefadroxil) possess structural features similar to those of the physiological oligopeptide substrates of the peptide transport system. Several ß-lactam antibiotics that lack protonatable amino groups (e.g., cefixime and cefdinir) are also transported. The intestinal peptide transporter accepts these antibiotic substrates and acts as a vehicle for their effective absorption. The pharmacological potency of these drugs is also determined by their half-life in the circulation, and the renal peptide transporter PepT2 mainly contributes to the active reabsorption of these antibiotics from the glomerular filtrate and as such increases their half-life in the circulation. The peptide transporters also mediate the uptake of other active peptides such as angiotensin-converting enzyme inhibitors (e.g., captopril), anticancer agents (e.g., Bestatin), and certain prodrugs (e.g., L-
-methyldopa-pro).
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Functional characteristics of PepT1
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The stoichiometry of PepT1 has emerged as a central experimental question. Because the transporter is capable of translocating neutral, cationic, and anionic substrates, investigators have examined whether the H+-to-substrate stoichiometry remains the same for those different classes of peptides. A number of studies have shown that PepT1-mediated transport of neutral and positively and negatively charged dipeptides is electrogenic (3, 13, 16). The calculated flux coupling ratio for the neutral dipeptide glycyl-sarcosine-to-H+ cotransport mediated by PepT1 in oocytes is 1:1 (3), and a similar stoichiometry was found for cationic dipeptides (Gly-Lys); interestingly, a charge-to-substrate coupling ratio of 2:1 for anionic dipeptides (Gly-Glu) was identified (16). These data suggest that the carboxylate groups of the anionic substrates are translocated in their protonated form.
In proton-coupled transporters, histidine residues have been found to play essential catalytic roles, since the imidazole ring in the histidine side chain is well adapted to act as a proton acceptor or donor at physiological pH. The significance of histidyl residues in the H+-oligopeptide transporters was initially identified in studies with renal and intestinal brush-border membrane vesicles, where transport activity was severely impaired following incubation with the histidine-specific agent diethylpyrocarbonate. These observations have been verified recently at the molecular level with the mutagenesis of highly conserved histidine residues in the cloned human PepT1 and PepT2 transporters (4; unpublished data). The results show that those histidine residues within the second putative transmembrane region of both PepT1 and PepT2 transporters (His-57 in PepT1 and the equivalent residue, His-87, in PepT2) are obligatory for substrate translocation (Fig. 2B). Species differences were observed when His-121 was substituted, leading to an elimination of cephalosporin and dipeptide transport in rat PepT1, whereas wild-type activity resulted in equivalent human PepT1 mutants. The importance of the amino terminus in substrate recognition was verified further with the analysis of a chimeric protein, which combined the amino terminus of PepT2 (high-affinity transporter) with the carboxy terminus of PepT1 (low-affinity transporter) (2). The resulting fusion protein retained the characteristics of PepT2 with respect to the substrate affinity and the pH dependence of transport, leading to the conclusion that, in contrast to SGLT1, the high-affinity substrate binding site of PepT2 is encoded by the amino-terminal region of the protein (transmembrane domains 1–9 in Fig. 2B).
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Biophysical analysis of transporter function
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The identification and isolation of the cDNA clones for SGLT and PepT family members lend great advantages to the detailed molecular analysis of transporter function. The negligible levels of endogenous Na+-glucose transporters and H+-oligopeptide transport activity in Xenopus laevis oocytes, combined with the overexpression of functional transporters, provide an ideal system for electrophysiological studies to address structure-function questions and to allow the generation of kinetic models in which individual reaction steps are defined.
A number of electrophysiological studies have focused on the intestinal and renal Na+-glucose transporters and the intestinal peptide transporter. Because the SGLT1 and PepT1 transporters are electrogenic and display transport processes that depend on membrane potential, studies have been carried out under two-electrode voltage-clamped condition (4, 9, 13, 16). In addition, a series of pre-steady-state kinetic measurements have been made using voltage-jump techniques (9, 13).
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A kinetic model for SGLT
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Experiments were carried out to measure the SGLT1 currents under two-electrode voltage-clamped condition, following manipulation of the external cation, sugar, and phlorizin (a competitive inhibitor of SGLT1-mediated transport) concentrations, and a model was proposed to account for the results (17). The experiments showed that sugar transport occurred only in the presence of external Na+ and increased at negative membrane potentials. In addition, each sugar molecule was cotransported with two Na+. In the presence of Na+ and absence of sugar, the application of phlorizin reduced the current to below the baseline, indicating the presence of a phlorizin-sensitive Na+ leak. The impact of this Na+ leak on the transport physiology is uncertain, but presumably it must impose a small penalty on the capacity of the transporter to concentrate substrate against a concentration gradient.
Additional refinement of the model was made possible with the measurement of pre-steady-state kinetics (Fig. 3A). The membrane potential was voltage clamped at -50 mV, and the voltage was stepped to test potentials, ranging from -150 to +50 mV. This produced transient relaxation currents, which were fitted to exponential functions to determine rate constants for the decay (
values). Integration of the transient currents yielded the charge transfer (Q value), and, when the data were fitted to the Boltzmann equation, a measure of the total charge (Qmax values) was obtained. These calculated values were compared with simulated transport models, allowing the assignment of values to certain steps in the reaction cycle. The transient currents observed for SGLT1 were attributed to a slow, voltage-sensitive reorientation of the empty carrier in the membrane, before binding or after Na+ binding/dissociation (Fig. 3A). It is proposed that the ions can either move near the extracellular surface or within (the "ion well" effect) the negatively charged transporter (17). Within the SGLT1 protein, the polar residue, D176, may play a role in this slow reorientation step (Fig. 3A), since substitution at this position with a nonpolar residue (D176A) altered charge transfer kinetic rates (17).
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A model for PepT1
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Additional studies on rabbit PepT1 extended the initial models proposed for SGLT1 (17), and subsequently for human PepT1 (9), by examining the influence of membrane potential and intracellular proton concentration on the transport process (Fig. 3B) (13). This revealed a striking symmetry of the pre-steady-state kinetics due to a single H+ binding site, which is accessible from both sides of the membrane. The data indicate that the H+ chemical potential and membrane potential determine its orientation in the membrane. Under normal conditions at the brush-border membrane, where the membrane potential is approximately -50 mV and the extracellular pH is acidic, the proton binding site is predicted to adopt an outwardly facing conformation. From a physiological perspective, this is appropriate, allowing the efficient binding of H+ and oligopeptide substrates at the apical side of the membrane followed by their translocation across the membrane.
A comparison of molecular models for SGLT1 and PepT1 (Fig. 3, A and B) identifies a number of common characteristics shared between Na+- and proton-dependent solute-coupled transporters. Both transporter proteins appear negatively charged overall and display ordered simultaneous transport models, in which the ion binds first. In both models, the presence of pre-steady-state kinetics is attributed to reorientation of the empty carrier in the membrane and to the ion binding and/or dissociation. Thus transporters from these families share basic mechanistic features, despite lack of significant sequence homology.
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Conclusions
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New insights into the molecular physiology of ion-coupled transporters have been obtained based on expression studies of cloned transporters in Xenopus oocytes. Extensive biophysical analyses of SGLT1 and PepT1, the archetypal members of the mammalian Na+-glucose and H+-oligopeptide transporter families, have provided new insights into their substrate specificity, coupling stoichiometry, and translocation mechanisms. Mutagenesis studies and characterization of patients with transporter defects have identified residues that participate in ion coupling, alter trafficking to the plasma membrane, define substrate recognition, and affect individual steps in the transport cycle.
Further biophysical analysis of these important proteins will undoubtedly contribute to our basic understanding of the role of ion-coupled transport in epithelial physiology. This may, in turn, prove useful in the identification, treatment, and management of diseases in which Na+-glucose transport function is impaired (e.g., GGM) and in the H+-oligopeptide transporter-mediated delivery of nutritionally important oligopeptides and pharmacologically active drugs.
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Top
Introduction
Na+-glucose transporters
µH) increased] and/or the membrane potential (Vm) is decreased, there is a shift toward more outwardly facing transporters (central arrow in B). This situation is predicted to occur under normal physiological conditions. The opposite shift, toward more inwardly facing transporters, occurs when intracellular pH is lowered (